The overall objective of the proposal is to elucidate the inhibitory mechanisms in colon carcinogenesis by the naturally occurring agents curcumin and phenylethyl-3-methylcaffeate (PEMC). Colon cancer is the second most common malignancy in the Western world. In the USA lone, 56,600 annual deaths are attributed to colon cancer. Recent evidence suggests that non-steroidal anti-inflammatory agents (NSAIDs), use of the drugs for the prevention of colon cancer is limited due to severe gastrointestinal and renal toxicity. Our studies and those by others indicate that curcumin and PEMC, which are present in turmeric and honey respectively, inhibit the metabolism of arachidonic acid (AA) and also block the formation of azoxymethane (AOM)-induced aberrant crypt foci and adenocarcinomas in the colon of rats. Both these agents possess anti-inflammatory and anti-tumor activities, but, importantly, they do not have the undesirable toxic side effects of the NSAIDs. Thus, it is important to delineate the precise mechanisms that lead to the specific effects by curcumin and PEMC which have promise as safer anti-cancer agents for humans. Several studies indicate that specific activities of enzymes that affect AA metabolism and the modification of certain transduction pathways lead to suppression of tumorigenesis in the colon by these agents. The propose study is aimed at the elucidation of inhibitory processes by examining the selectivity of effects of curcumin and PEMC on enzymes involved in AA metabolism during several stages of AOM-induced colon carcinogenesis in the rat model. Specifically, we will examine the effects of natural curcumin and PEMC on both expression (RNA and protein levels) and activities of inducible nitric oxide synthases (iNOS), cyclooxygenase (COX) isoforms, and of lipoxygenase (LOX)-mediated metabolism and 12-LOX expression in colonic mucosa and in colon tumors of male F344 rats during defined stages of carcinogenesis. Tissue distribution and comparative metabolism studies of curcumin and PEMC will be studied with synthetic [3H] curcumin and [3H]-PEMC in vivo in male F-344 rats.